The protein tyrosine kinases (PTKs) are a family of proteins that catalyze phosphorylation of tyrosine residues in target proteins; PTKs play important roles in cellular signaling. Within this large family of proteins is the ERBB PTK family, which consists of four receptor kinases, ERBB1 (EGFR1, HER1), ERBB2 (c-Neu, HER2), ERBB3 (HER3) and ERBB4 (HER4). The ERBB kinases regulate a wide range of cellular responses, including cell proliferation, survival, migration and differentiation. ERBB signaling pathways are known to be altered in a wide variety of cancers, which has led to the development of drugs to specifically inhibit activity of members of this family (Junttila et al., Cancer Res. 65(4):1384-1393, 2005).
ERBB4 is a protein of approximately 180 kD and is expressed as four alternatively spliced isoforms. Previous studies of the role of ERBB4 in cancer development and prognosis have produced differing and sometimes contradictory results. For example, clinical studies of breast cancer have linked ERBB4 expression to either a favorable or adverse clinical outcome, and in vitro studies have suggested that in breast cancer cells, ERBB4 mediates either differentiation or tumorigenic growth (Junttila et al., Cancer Res. 65(4):1384-1393, 2005).
Cutaneous malignant melanoma is the most common fatal skin cancer (Jermal et al., CA Cancer J. Clin. 156(2):106-130, 2006; Tsao et al., N. Engl. J. of Med. 351:998-1012, 2004), and the incidence of this disease increases each year. Patients diagnosed with malignant melanoma have an average survival time of less than 10 months. PTKs are frequently mutated in cancer, and since they are amenable to pharmacologic inhibition (Futreal et al., Nat. Rev. Cancer 4:177-183, 2004; Sawyers, Nature 432:294-297, 2004), further analysis of the PTK gene family is needed to provide insight into melanoma pathogenesis and to identify new therapeutic strategies. Given the known role of PTKs in human cancer, and the disparate findings of studies of ERBB4 in cancer development, it is desirable to further evaluate ERBB4 in patients with malignant melanoma.